Cabazitaxel Drug Monograph

Cabazitaxel Monograph

Cabazitaxel (Jevtana) National Drug Monograph March 2011 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary: Cabazitaxel is a novel taxane that shows anticancer activity against docetaxel sensitive and resistant cells in vitro. It is thought to be a weak substrate for p-glycoprotein, the main mechanism for taxane resistance.

It was approved by the FDA, in combination with prednisone, for the treatment of patients with castrate-resistant prostate cancer who progressed during or following therapy with a docetaxel containing regimen.

Efficacy In a phase III trial comparing cabazitaxel (25mg/m2) plus prednisone to mitoxantrone (12 mg/m2) plus prednisone in patients with castrate-resistant prostate cancer who progressed during or following therapy with at least 225 mg/m2 of docetaxel (suggesting a minimum of 12 weeks of treatment), cabazitaxel met its primary endpoint of increasing overall survival. The median overall survival of 15.1 months for cabazitaxel versus 12.7 months for mitoxantrone represents a 30% decrease in the relative risk of death (Hazard Ratio 0.70 95%CI 0.59-0.83).

Safety There was a higher incidence of treatment related deaths in the cabazitaxel arm. The most common fatal adverse event was infection in 5 patients, 4 of whom had neutropenia and 1 with neutropenic fever. Four of the five fatal infections occurred after one dose. The fatal adverse event in 4 patients was renal failure.

Serious adverse events included: neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.

Boxed warnings exist for neutropenic deaths and hypersensitivity reactions. Cabazitaxel is contraindicated in patients with a previous history of hypersensitivity reactions to drugs formulated with polysorbate 80.

Introduction

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 1 Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up Cabazitaxel Monograph

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating cabazitaxel for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics Cabazitaxel is new generation taxane. It binds to microtubules promoting tubulin assembly, stabilizes microtubules resulting in cell cycle arrest, and inhibits cell proliferation. In pre-clinical trials, cabazitaxel had activity in docetaxel sensitive and docetaxel resistant cell lines and was shown to cross the blood brain barrier. The most widely studied mechanism of inherited and acquired multidrug resistance to taxanes is over expression of p-glycoprotein. Sensitivity of docetaxel-resistant cell lines to cabazitaxel suggests it is a weak substrate for p-glycoprotein.

Table #1 Cabazitaxel Pharmacokinetics Parameter Drug Extensively in liver, primarily CYP3A4/5 and to a lesser extent CYP2C8. 3 active metabolites and 17 others identified; all are excreted in urine and feces. Metabolism Cabazitaxel is not a CYP inducer and has a low potential to inhibit drugs that are substrates for CYP isoenzymes 80% of IV dose eliminated within 2 weeks, mainly excreted in feces as Elimination metabolites; 3.7% of an IV dose is eliminated renally Three compartment model with  half-life=4 minutes, β half-life=2 hours, and γ Half-life half-live=95 hours.

FDA Approved Indication(s) Indicated in combination with prednisone for the treatment of patients with hormone-refractory prostate cancer previously treated with docetaxel-containing treatment regimen.

Potential Off-label Uses This section is not intended to promote any off-label uses. Off-label use should be evidence- based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA PBM Intranet site only).

First-line therapy of hormone-refractory (castrate-resistant) prostate cancer in place of docetaxel.

Current Alternatives Cabazitaxel is the only drug with an FDA indication for castrate-resistant prostate cancer in patients who progressed during or following therapy with a docetaxel containing regimen. Multiple regimens have been studied in patients with taxane resistant disease, but none have provided a survival benefit. The best alternative to cabazitaxel therapy is participation in a clinical trial.

Dosage and Administration Pre-medications (at least 30 minutes prior to cabazitaxel to reduce the risk/severity of hypersensitivity reactions):

 Antihistamine IV (e.g. diphenhydramine 25mg or equivalent)  Corticosteroid IV (dexamethasone 8mg or equivalent)

 H2 antagonist IV (ranitidine 50mg or equivalent)

Preparation  First Dilution- Mix the vial of cabazitaxel 60mg/1.5ml with the entire contents of the supplied diluents. Limit foaming during dilution; do not shake. Final concentration of cabazitaxel is 10mg/mL.  Second Dilution- Withdraw the recommended dose from First Dilution and further dilute in 250mL PVC-free container with either 0.9% sodium chloride solution or 5% dextrose solution. If a dose needed is greater than 65 mg, use a larger volume of infusion solution so that the concentration of cabazitaxel does not exceed 0.26 mg/mL. The final concentration of cabazitaxel should be between 0.1 mg/mL and 0.26 mg/mL. Use this final solution within 8 hours stored at room temperature or within a total of 24 hours if refrigerated (included infusion time).

Dose  Initial dose of 25 mg/m2 over 1 hour as an intravenous infusion every three weeks in combination with prednisone 10 mg orally daily throughout treatment  Dose Modifications- reduce dose to 20 mg/m2 if patient experiences any of the following toxicities: Toxicity Dosage Modification Prolonged Grade ≥Grade 3 neutropenia Delay treatment until neutrophil count is (greater than 1 week) despite appropriate >1,500 cells/mm3, then reduce dose to 20 medication including G-CSF mg/m2. Use G-CSF secondary prophylaxis Febrile neutropenia Delay treatment until improvement or resolution, and until neutrophil count is >1,500 cells/mm3, then reduce dose to 20 mg/m2. Use G-CSF secondary prophylaxis Grade ≥ 3 diarrhea or persisting diarrhea Delay treatment until improvement or despite appropriate medications, fluids, and resolution, then reduce dose to 20 mg/m2. electrolyte replacement

Use in Special Populations  Renal Impairment- No formal trials have been conducted in patients with renal impairment. Population pharmacokinetic trials included patients with mild to moderate renal impairment; no meaningful effects were seen on the pharmacokinetics of cabazitaxel. No data are available on the use in patients with severe renal impairment or end-stage renal disease.  Hepatic Impairment- No formal trials have been conducted in patients with hepatic impairment. Cabazitaxel is extensively metabolized by the liver; hepatic impairment is likely to increase cabazitaxel concentrations.

Efficacy

Efficacy Measures

Primary  Overall Survival (Date of randomization to death)

Secondary  Progression Free Survival (a composite endpoint of time from randomization to the first date of progression [PSA progression, tumor progression, pain progression] or death.  PSA Response (reduction in PSA serum concentration of ≥50% if baseline PSA is ≥ 20 mcg/L)  PSA progression (increase of ≥25% over nadir PSA if the increase in the absolute value is ≥5 mcg/L in men with no PSA response or ≥50% over nadir for patients showing a PSA response)  Objective Tumor Response (in patients with measurable disease)  Pain Response (for patients with a present pain intensity [PPI] score of ≥2 or a mean analgesic score of ≥10 points at baseline or both) defined as a reduction of 2 points or more from baseline median PPI score without increasing analgesic score or decrease of more than 50% in analgesic use without an increase in pain, maintained for 3 weeks or more.  Pain Progression (increase in median PPI score of ≥1 point from reference value or an increase of ≥25% in the mean analgesic score or requiring palliative radiotherapy.  Time to Tumor Progression (number of months from randomization until evidence of progressive disease by RECIST criteria).

Summary of efficacy findings Phase III TROPIC trial: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration- resistant prostate cancer progressing after docetaxel treatment.1

Study Design  International (26 countries)  Centrally randomized  Open-label to patients and treating physicians  Study team blinded to data analysis

Inclusion Criteria  Pathologically proven prostate cancer  Documented disease progression during or after completion of docetaxel therapy o Measurable disease- required documented disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) with at least one visceral or soft tissue metastatic lesion o Non-measurable disease- rising serum PSA (at least 2 consecutive increases relative to a reference value at least 1 week apart) or the appearance of at least one new radiographic lesion  ECOG Performance Status 0-2  Prior and on-going castration by orchiectomy or LHRH agonist or both  Antiandrogen withdrawal followed by progression at least 4 weeks (6 weeks in the case of bicalutamide) prior to enrollment  Adequate hematological, hepatic, renal and cardiac function  LVEF more than 50% assessed by MUGA or Echocardiogram  Concomitant use of bisphosphonates if the dose was stable for 12 weeks before enrollment  LHRH therapy mandated to be continued throughout trial

Exclusion Criteria

 Previous mitoxantrone therapy,  Radiotherapy to 40% or more of bone marrow  Cancer therapy (other than LHRH analogues) within 4 weeks of enrollment  Grade 2 or higher peripheral neuropathy or stomatitis  Other serious illness (including secondary cancers)  History of hypersensitivity to polysorbate 80-containing drugs or prednisone  Amendment after first 59 patients: Patients receiving a cumulative dose of docetaxel lower than 225 mg/m2 (equivalent to 12 weeks of treatment)

Treatment  All patients received prednisone 10mg daily ( or equivalent dose of prednisolone)  Randomized to either cabazitaxel 25 mg/m2 IV over 1 hour or mitoxantrone 12 mg/m2 IV over 15-30 minutes  Cabazitaxel patients were pre-treated with a single dose of IV antihistamine, corticosteroids

(8 mg dexamethasone or equivalent) and H2 antagonist (except cimetidine) 30 minutes before cabazitaxel.  Treatment was repeated every 21 days for a maximum of 10 cycles  Crossover to cabazitaxel was not allowed for the mitoxantrone group  Prophylactic G-CSF was not allowed for the 1st cycle but was allowed after the first occurrence of either neutropenia lasting more than 7 days or neutropenia complicated by fever or infection.

Baseline Patient Characteristics Table #2 Baseline Characteristics Mitoxantrone Cabazitaxel Characteristic N=377 N=378 Age, median 67 (61-72) 68 (62-73) ≥75 years old 19% 18% White 83% 84% Asian 8% 7% Black 5% 5% ECOG 0 or 1 91% 93% Metastatic Disease 94% 96% Bone metastases 87% 80% Visceral metastases 25% 25% Pain at baseline 45% 46% Previous therapy Hormonal 99% 99% Number of chemotherapies 1 71% 69^ 2 21% 25% >2 8% 6% Radiation 59% 61% Surgery 54% 52% Total dose docetaxel (mg/m2) median 529.2 576.6 Progression relative to docetaxel During treatment 28% 30% <3 months from last dose 48% 42% ≥3 months from last dose 24% 27% Median time from last docetaxel dose to disease progression (months) 0.7 (IQR 0.0-2.9) 0.8 (IQR 0.0-3.1)

Primary and Secondary Outcomes

Table #3 Results Result Mitoxantrone Cabazitaxel Hazard Ratio P value for (95%CI) comparison Median Follow-up = 12.8 months (IQR 7.8-16.9) Median Overall 12.7 months 15.1 months 0.70 <0.0001 Survival (95%CI 11.6-13.7) (95%CI 14.1-16.3) (0.59-0.83) Median Progression 1.4 months 2.8 months 0.74 <0.001 Free Survival (95%CI 1.4-1.7) (95%CI 2.4-3.0) (0.64-0.86) Tumor response rate 4.4% 14.4% - 0.0005 PSA response rate 17.8% 39.2% - 0.0002 Pain response rate 7.7% 9.2% - 0.63 Median time to 5.4 months 8.8 months 0.61 <0.0001 tumor progression (95%CI 2.3-10.0) (95%CI 3.9-12.0) (0.49-0.76) Median time to PSA 3.1 months 6.4 months 0.75 0.001 progression (95%CI 0.91-9.1) (95%CI 2.2-10.1) (0.63-0.9) Median time to pain Not reached 11.1 months 0.91 0.52 progression (95%CI 2.9- not (0.69-1.19) reached) Median Duration of 4 cycles 6 cycles Therapy

Mortality

Table #4 Deaths during therapy Events Mitoxantrone N=371 Cabazitaxel N=371 Total deaths 74% 61% Deaths ≤30 days after last dose of study drug 9 (2%) 18 (5%) Cause: Disease Progression 6 (2%)* 0 Adverse events Neutropenia & clinical consequence/sepsis 1 (<1%) 7 (2%) Cardiac 0 5 (1%) Dyspnea 1 (<1%) 0 Dehydration/electrolyte imbalance 0 1 (<1%) Renal failure 0 3 (1%) Cerebral hemorrhage 0 1 (<1%) Unknown cause 0 1 (<1%) Motor vehicle accident 1 (<1%) 0 Deaths >30 days after last dose of study drug 72% 56% *includes three patients whose deaths were reported as an adverse event coded as disease progression

A subgroup analysis of overall survival was performed defined by baseline characteristics. The median overall survival for all subgroups favored cabazitaxel. However, for several subgroups the 95% confidence intervals crossed over 1. Some that crossed 1 had small numbers of patients with wide confidence intervals (e.g. ECOG status 2 and Total docetaxel dose < 225 mg/m2). Of note, the Median Overall Survival for the subgroup Progression ≥3 months after docetaxel treatment favored cabazitaxel but the upper bound of the confidence interval crossed 1.

Disease progression was the primary reason for discontinuation in both groups (Mitoxantrone 71%, Cabazitaxel 48%) followed by adverse event (Mitoxantrone 8%, Cabazitaxel 18%). Twenty-eight percent of cabazitaxel patients completed all 10 cycles versus 12% in the mitoxantrone group. There is no information on treatment received following disease progression in the cabazitaxel arm; in the mitoxantrone arm it is noted that 12% of patients received a tubulin-

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 6 Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up Cabazitaxel Monograph binding drug following disease progression. There is no information about the collection of any quality of life data.

An analysis of the incidence of neutropenia and diarrhea (all grades) in subgroups of patients receiving cabazitaxel found differences in the rates of adverse events by age, prior radiotherapy, and geographic location. The incidence of neutropenia was greater outside of North America and Europe, likely due to differences in investigator treatment of neutropenia and febrile neutropenia.

Supporting Data

Following pre-clinical data in indicating antitumor activity in docetaxel sensitive and resistant cell lines and human xenografts, a phase I trial was initiated in patients with solid tumors refractory to conventional therapy. Patients were eligible if they received less than two prior chemotherapy regiments for metastatic disease. Two of twenty-five patients showed anti-tumor responses; both patients had metastatic prostate cancer and one was resistant to prior docetaxel therapy.2

Adverse Events (Safety Data) 3 Table #5 Adverse Events in ≥5% of patients receiving cabazitaxel plus prednisone or mitoxantrone plus prednisone Cabazitaxel plus prednisone Mitoxantrone plus prednisone N=371 N=371 All Grades Grades 3-4 All Grades Grades 3-4 % % % % Blood and lymph Neutropenia 94 82 87 58 Febrile neutropenia 7 7 1 1 Anemia 98 11 82 5 Leukopenia 96 69 93 42 Thrombocytopenia 48 4 43 2 Cardiac Arrhythmia 5 1 2 <1 GI Disorders Diarrhea 47 6 11 <1 Nausea 34 2 23 <1 Vomiting 22 2 10 0 Constipation 20 1 15 <1 Abdominal pain 17 2 6 0 Dyspepsia 10 0 2 0 General Fatigue 37 5 27 3 Asthenia 20 5 12 2 Pyrexia 12 1 6 <1 Peripheral edema 9 <1 9 <1 Mucosal inflammation 6 <1 3 <1 Pain 5 1 5 2 Infections Urinary tract infection 8 2 3 1 Weight decreased 9 0 8 <1 Metabolism and nutrition Anorexia 16 <1 11 <1 Dehydration 5 2 3 <1 Musculoskeletal Back pain 16 4 12 3 Arthalgia 11 1 8 1

Muscle spasms 7 0 3 0 Nervous system Peripheral neuropathy 13 <1 3.2 <1 Dysgeusia 11 0 4 0 Dizziness 8 0 6 <1 Headache 8 0 5 0 Renal and Urinary Hematuria 17 2 4 <1 Dysuria 7 0 1 0 Respiratory Dyspnea 12 1 4 <1 Cough 11 0 6 0 Skin Alopecia 10 0 5 0 Vascular Hypotension 5 <1 2 <1

Median Duration of Therapy 6 cycles 4 cycles

Deaths and Other Serious Adverse Events Deaths due to causes other than disease progression within 30 days of last study drug occurred in 18 cabazitaxel patients and 3 mitoxantrone patients.  Most common fatal adverse reactions in cabazitaxel patients- infections (n=5 cases of sepsis or septic shock; all had grade 4 neutropenia and one had febrile neutropenia) and renal failure (n=4); 4 out of 5 fatal infection-related adverse events occurred after a single cabazitaxel dose. Other fatal reactions included ventricular fibrillation, cerebral hemorrhage, and dyspnea.  3 patients with a fatal adverse reaction were less than 65 years old; 15 were greater than or equal to 65 years old. Patients greater than or equal to 65 years old are more likely to experience certain adverse events, for example neutropenia and febrile neutropenia

Grade 3-4 serious adverse reactions: neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, asthenia.

Common Adverse Events (≥ 10%)  Anemia  Leukopenia  Neutropenia  Thrombocytopenia  Diarrhea  Fatigue  Nausea  Vomiting  Constipation  Asthenia  Abdominal pain  Hematuria  Back pain  Anorexia  Peripheral neuropathy  Pyrexia

 Dyspnea  Dysguesia  Cough  Arthalgia  Alopecia

Other Adverse Events

Table #6 Events in Elderly population Event Age ≥65 years old Age < 65 years old % % Grades 1-4 Fatigue 40 30 Neutropenia 97 89 Asthenia 24 15 Pyrexia 15 8 Dizziness 10 5 Urinary tract infection 10 3 Dehydration 7 2 Grade 3-4 Neutropenia 87 74 Febrile neutropenia 8 6

Tolerability Table #7 Discontinuations/delays/dose reductions due to adverse events Cabazitaxel plus prednisone Mitoxantrone plus prednisone % % Discontinuation 18 8 Dose Delays 28 15 Dose Reductions 12 4 Most common adverse events leading to discontinuations in cabazitaxel patients: neutropenia (2%) and renal failure.

Contraindications  Do not administer cabazitaxel if the neutrophil count is less than or equal to 1,500/mm3.  Do not administer cabazitaxel in patients with a history of severe hypersensitivity reactions to cabazitaxel or other drugs formulated with polysorbate 80.

Warnings and Precautions 1. Neutropenia (Boxed Warning)  Five patients with grade 4 neutropenia, one with febrile neutropenia, experienced fatal infections. One additional death was attributed to neutropenia without a documented infection.  G-CSF may be administered to decrease the risk of neutropenia complications.

 Primary prophylaxis with G-CSF should be considered in patients at high risk who are pre- disposed to increased complications from prolonged neutropenia. This includes: patients >65 years old, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious co-morbidities.  Monitor complete blood counts weekly during Cycle 1 and before each subsequent cycle to assess if a dose adjustment is needed.  If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite the use of G-CSF, reduce the dose of cabazitaxel to 20 mg/m2 and restart treatment when the neutrophil count recovers to a level > 1,500/mm3.

2. Hypersensitivity Reactions (Boxed Warning)

 Pre-medicate all patients with an IV antihistamine, corticosteroid, and H2 blocker prior to administration of cabazitaxel.  Observe patients closely for hypersensitivity reactions especially during the 1st and 2nd infusions. Hypersensitivity reactions may occur within a few minutes of starting the cabazitaxel infusion; facilities and equipment for treating bronchospasm and hypotension should be available.  Severe hypersensitivity reactions, including generalized rash/erythema, hypotension, and bronchospasm require discontinuation of the cabazitaxel infusion and appropriate therapy.

3. Gastrointestinal Symptoms  Nausea, vomiting, and severe diarrhea have been reported  Death as a result of severe diarrhea and electrolyte imbalance occurred in clinical trials.  Patients with severe diarrhea should be treated with rehydration and antidiarrheals as needed.  Treatment delay or dose reduction may be needed for Grade ≥3 diarrhea.

4. Renal Failure  Renal failure was reported in clinical trials.  Four cases of renal failure resulted in death.  Most cases are associated with sepsis, dehydration, or obstructive uropathy.

5. Hepatic Failure  Patients with impaired hepatic function were excluded from clinical trials. No dedicated trials in patients with hepatic impairment have been conducted.  Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs in the taxane class.  Do not administer cabazitaxel to patients with hepatic impairment (total bilirubin ≥ the Upper Limit of Normal, or AST and/or ALT ≥1.5 times the Upper Limit of Normal).

6. Elderly  2% of patients under age 65 and 6% of patients greater than or equal to age 65 died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients greater than or equal to age 65 are more likely to experience certain adverse reactions including neutropenia and febrile neutropenia.

7. Pregnancy

 Pregnancy Category D; cabazitaxel may cause fetal harm when administered to pregnant women  Cabazitaxel is embryotoxic, fetotoxic, and abortifacient at exposure levels in rats and rabbits significantly lower than those expected at recommended human dosage levels.  There are no adequate or well controlled trials in pregnant women. Inform patient of the potential harm to the fetus if administered during pregnancy or if the patient becomes pregnant while receiving cabazitaxel.

8. Nursing Mothers  Cabazitaxel and its metabolites are excreted in the breast milk of lactating rats. It is not known if it is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made to either discontinue nursing or discontinue the drug taking into account the benefit versus risk for the mother.

Postmarketing Safety Experience (Optional) No data

Sentinel Events No data on sentinel events in the VHA database or on the Joint Commission web site.

Look-alike / Sound-alike (LA / SA) Error Risk Potential

As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name Cabazitaxel: docetaxel, paclitaxel LA/SA for trade name Jevtana: Jantoven, Januvia Drug Interactions

Drug-Drug Interactions  No formal drug-drug interaction trials have been conducted  Prednisone or prednisolone at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.  Drugs that may Increase cabazitaxel plasma concentrations o CYP3A4 Inhibitors: cabazitaxel is primarily metabolized through CYP3A, but there are no formal trials of concomitant use with strong CYP3A4 inhibitors. o Strong inhibitors (e.g. ketoconazole, intraconazole, clarithromycin, atazanavir, indivavir, nefazodone, nelfinavir, ritoniavir, saquinavir, telithromycin, voriconazole) are expected to increase cabazitaxel concentrations and co-administration should be avoided. o Exercise caution with the co-administration of moderate CYP3A4 inhibitors.  Drugs that may Decrease cabazitaxel plasma concentrations o CYP3A4 inducers: There are no formal drug interaction trials of concomitant use with strong CYP3A4 inducers.

o Strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital) are expected to decrease cabazitaxel concentrations and co-administration should be avoided. o Patients should also avoid co-administration of St. John’s Wort.

Drug-Lab Interactions No data.

Acquisition Costs

Table #8 Cabazitaxel Acquisition Costs (as of January 2011) Drug Dose Cost/Cycle/patient ($) Cost/6 Cycles/patient ($) Cabazitaxel 25 mg/m2 IV every 21 5899.16 35,394.96 days Docetaxel 75 mg/m2 IV every 21 1899.04 11,394.24 days Mitoxantrone 12 mg/m2 IV every 21 66.80-319.79 400.80-1918.74 days

Pharmacoeconomic Analysis There are no published Pharmacoeconomic data for the use of cabazitaxel as second-line chemotherapy in castrate-resistant prostate cancer.

Conclusions

Clinical Efficacy Cabazitaxel, in combination with prednisone, is the first drug therapy to show a survival advantage in patients with docetaxel resistant metastatic prostate cancer.

In a randomized phase III trial in patients with castrate-resistant prostate cancer who had disease progression during or following therapy with docetaxel, cabazitaxel, a novel taxane, improved survival by 2.4 months compared to mitoxantrone therapy, a 30% reduction in relative risk of death (hazard ratio 0.70). There was also improvement in many of the secondary outcomes. A subgroup analysis by baseline characteristics found a survival advantage for all subgroups that favored cabazitaxel, however some groups were small and the upper bound of the 95% confidence interval crossed 1. Patients in the cabazitaxel group completed a median of 6 cycles of therapy versus 4 cycles in the mitoxantrone group. Disease progression was the primary reason for discontinuation of therapy in both groups. Discontinuation rates due to adverse events were higher in the cabazitaxel group. There is no information on quality of life data. Data on subsequent therapy after disease progression or discontinuation in the cabazitaxel group was not provided.

The study population in the clinical trial was similar to the VA population with the exceptions of a high percentage with an ECOG Performance Status of 0-1 and the exclusion of patients with pre-existing serious illness or grade 2 or higher peripheral neuropathy or stomatitis. Patients greater than 65 years old are more likely to experience some adverse events, for example Grade 3-4 neutropenia and febrile neutropenia.

Clinical Safety

Common adverse events in the clinical trial included hematologic events and diarrhea. The most frequent serious hematologic adverse events were neutropenia, leukopenia, and anemia.

There is a boxed warning for neutropenia deaths and hypersensitivity reactions during administration. Blood count monitoring for neutropenia on a regular basis is recommended.

Treatment related mortality was higher in the cabazitaxel group (5% versus 2% in mitoxantrone). The most frequent cause of cabazitaxel related mortality was neutropenia with fever or sepsis. Treatment of neutropenia varied geographically. Prophylactic use of G-CSF was not allowed, but secondary use was allowed. There is no information on the actual use of G-CSF in the trial or the median duration of neutropenic episodes.

Diarrhea accompanied by electrolyte imbalance requires prompt action and an established plan for management and patient education.

References:

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 13 Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up STRICTLY CONFIDENTIAL PRE-DECISIONAL DELIBERATION Insert Generic Drug Name Here Monograph INFORMATION

Prepared March 2011 Contact person: Mark C. Geraci, Pharm.D., BCOP Clinical Pharmacy Specialist

DRAFT Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 14 Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up to $20,000 for unauthorized disclosure. 1 de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J-P, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147-54. 2 Mita AC, Denis LJ, Rowinsky EK, deBono JS, Goetz AD, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009;15:723-730. 3 Jevtana (cabazitaxel) Injection. Product Package Insert. Sanofi-Aventis; Bridgewater, NJ: June 2010.